Nitric oxide signalling underlies salicylate-induced increases in neuronal firing in the inferior colliculus: a central mechanism of tinnitus?

Abstract

The tinnitus-inducing agent salicylate reduces cochlear output but causes hyperactivity in higher auditory centres, including the inferior colliculus (the auditory midbrain). Using multi-electrode recording in anaesthetised guinea pigs (Cavia porcellus), we addressed the hypothesis that salicylate-induced hyperactivity in the inferior colliculus involves nitric oxide signalling secondary to increased ascending excitatory input. In the inferior colliculus, systemic salicylate (200 mg/kg i.p., 0 h) markedly increased spontaneous and sound-driven neuronal firing (3-6 h post drug) with both onset and sustained responses to pure tones being massively increased. Reverse microdialysis of increasing concentrations of salicylate directly into the inferior colliculus (100 μM-10 mM, from 0 h) failed to mimic systemic salicylate. In contrast, it caused a small, transient, increase in sound-driven firing (1 h), followed by a larger sustained decrease in both spontaneous and sound-driven firing (2-5 h). When salicylate was given systemically, reverse microdialysis of the neuronal nitric oxide synthase inhibitor L-methyl arginine into the inferior colliculus (500 mM, 2-6 h) completely blocked the salicylate-induced increase in spontaneous and sound-driven neuronal firing. Our data indicate that systemic salicylate induces neuronal hyperactivity in the auditory midbrain via a mechanism outside the inferior colliculus, presumably upstream in the auditory pathway; and that the mechanism is ultimately dependent on nitric oxide signalling within the inferior colliculus. Given that nitric oxide is known to mediate NMDA receptor signalling in the inferior colliculus, we propose that salicylate activates an ascending glutamatergic input to the inferior colliculus and that this is an important mechanism underlying salicylate-induced tinnitus.

Local targets of T‐stellate cells in the ventral cochlear nucleus

“…Somehow, this upregulation is presumed to be In salicylate-induced tinnitus, a significant increase in the number of nNOS-expressing VCN principal neurons has also been noted (Zheng et al, 2006), and as a result, there is thought to be a progressive amplification of the neural response to sound as one ascends to the IC, medial geniculate, and auditory cortex (for review, see Salvi et al, 2021). Interestingly, one recent study of salicylate-induced tinnitus points to the T-stellate input to the IC as the instigator of this amplification (Olthof et al, 2021). In tinnitus generated by systemic application of salicylate, extracellular recordings from cells in the ICC showed an increase in both spontaneous and driven firing rates that was blocked by an NOS inhibitor injected into the IC.…”